Variant classification summary

NM_012289.4:c.445G>A

KEAP1 · NP_036421.2:p.(Glu149Lys) · NM_012289.4

GRCh37: chr19:10610265 C>T · GRCh38: chr19:10499589 C>T

Gene: KEAP1 Transcript: NM_012289.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Glu149Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_012289.4:c.445G>A (p.Glu149Lys) is a missense variant in KEAP1. This variant has been observed in somatic cancers (COSMIC, n=5) but has not been reported in ClinVar and is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

2

The variant is absent from gnomAD in all assessed populations, meeting PM2 at supporting strength.

3

Computational evidence supports a benign effect: BayesDel score of 0.0063572 strongly predicts benign, REVEL score of 0.487 is below the pathogenic threshold, and SpliceAI predicts no splice alteration (max delta 0.00). BP4 is met at supporting strength.

4

No functional studies, case-control data, de novo observations, segregation data, or ClinVar classifications are available for this variant. No published literature (PMIDs) was identified that directly mentions NM_012289.4:c.445G>A.

5

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as either likely pathogenic or likely benign under generic ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_012289.4:c.445G>A (p.Glu149Lys) is a missense substitution and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable for missense variants under PMC6185798.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at codon 149 resulting in the same amino acid substitution (p.Glu149Lys) with established pathogenicity. No ClinVar entries at this residue were identified.	clinvar
PS2	N/A	No de novo data available; no family studies or parental testing reported for this variant.
PS3	Not met	No well-established functional studies identified for this variant. OncoKB classifies NM_012289.4:c.445G>A (p.E149K) as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No PMIDs citing functional data for this variant were found.	oncokb
PS4	N/A	No case-control studies or prevalence data available for this variant in affected versus unaffected populations.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). Not applicable.
PM1	Not met	Codon 149 is not located in a statistically significant mutational hotspot in KEAP1. Cancer Hotspots analysis confirmed this residue is not significant.
PM2	Met	NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold (allele frequency < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue (Glu149) comparator missense variants with established pathogenicity were identified in ClinVar. The PM5 candidate harvesting pipeline found zero candidates and marked PM5 as not applicable for this variant.	pm5_candidates clinvar
PM6	N/A	No de novo observation reported for this variant. PM6 requires a de novo finding (with or without confirmed maternity/paternity, depending on strength level).
PP1	N/A	No co-segregation data available. No family studies have been reported for KEAP1 p.E149K.
PP2	Not assessed	KEAP1 is not included in the HCI prior database; no gene-level missense constraint metrics (z-score, missense intolerance score) are available to assess whether KEAP1 has a low rate of benign missense variation. PP2 cannot be evaluated without these data.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.487 (below the 0.5 threshold for pathogenicity) and BayesDel score is 0.0063572, which strongly predicts a benign effect. SpliceAI max delta score is 0.00, indicating no splicing impact.	revel bayesdel spliceai
PP4	N/A	No patient phenotype or clinical data provided. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar; OncoKB classifies it as 'Unknown Oncogenic Effect.'	clinvar oncokb
BA1	Not met	NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold (allele frequency > 1% per non-VCEP cutoff).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_012289.4:c.445G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the non-VCEP BS1 threshold (allele frequency > 0.3%).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	No data on observation of this variant in healthy adults with full penetrance expected. BS2 requires observation in a healthy adult individual for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrating no damaging effect for this variant. No functional data for p.E149K were identified.	oncokb
BS4	N/A	No segregation data available. BS4 requires lack of segregation in affected family members.
BP1	Not met	KEAP1-associated familial multinodular goiter is caused by both truncating and missense variants (PMID:39373520 reports p.Q86*, p.L136P, p.V411fs, p.R415C, p.R483H). Missense variants are a known mechanism of disease in KEAP1, so BP1 (missense in a gene where primarily truncating variants cause disease) does not apply.
BP2	N/A	No data on observation of this variant in trans with a pathogenic variant. BP2 is not assessable.
BP4	Met	Multiple lines of computational evidence support a benign effect. BayesDel score is 0.0063572, which is strongly predictive of a benign impact. REVEL score is 0.487, below the 0.5 threshold for deleterious prediction. SpliceAI max delta score is 0.00, indicating no splice alteration.	revel bayesdel spliceai
BP5	N/A	No data indicating this variant was found in a case with an alternate molecular basis for disease. BP5 cannot be assessed.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_012289.4:c.445G>A is a missense variant (p.Glu149Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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